Agency Response Letter for GRAS Notice No. GRN 000471
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CFSAN/Office of Food Additive Safety
May 13, 2014
John R. Endres, ND
Chief Scientific Officer
AIBMR Life Sciences, Inc.
4117 South Meridian
Puyallup, WA 98373
Re: GRAS Notice No. GRN 000471
Dear Dr. Endres:
The Food and Drug Administration (FDA) is responding to the notice, dated May 2, 2013, that you submitted on behalf of American River Nutrition, Inc. (ARN), in accordance with the agency’s proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on May 7, 2013, filed it on May 17, 2013, and designated it as GRAS Notice No. GRN 000471. In a letter dated September 11, 2013, ARN provided FDA with clarifying information and amended the scope.
The subject of the notice is annatto (Bixa orellana L.) seed oil-derived tocotrienols with δ-tocotrienol and γ-tocotrienol as the principal components(T3 extract). The notice informs FDA of the view of ARN that T3 extract is GRAS, through scientific procedures, for use as an ingredient in baked goods, beverages, cereals, chewing gum, dairy analogs, frozen dairy desserts, milk, milk products, nutritional bars, nuts, and processed fruits at levels up to 40 milligrams per kilogram (mg/kg) of food; and in fats and oils at levels up to 160 mg/kg of food.
ARN describes the identity and composition of T3 extract. The ingredient is an orange-red oil that contains a minimum of 70% tocotrienols, approximately 10% fatty acids, and 20% annatto oleoresins.
ARN describes the manufacturing process for T3 extract. The starting material is annatto seed oil. ARN states that an edible vegetable oil is added to the annatto seed oil as a carrier oil during the distillation process. This solution is subjected to a multi-stage, wiped-film distillation to isolate tocotrienols. The final product is standardized to a minimum concentration of 70% tocotrienols by the addition of edible vegetable oil.
ARN provides specifications for T3 extract, including minimum tocotrienol content (≥ 70%, of which δ-tocotrienol comprises 84 to 92% and γ-tocotrienol comprises 8 to 16%). ARN provides limits for moisture (≤ 1%), arsenic (≤ 2 mg/kg), lead (≤ 0.5 mg/kg), mercury (≤ 1 mg/kg), and cadmium (≤ 2 mg/kg). ARN also provides limits for microbial contaminants. ARN also states that the levels of the pigments bixin and norbixin in the extract are limited to less than 0.001%. ARN reports that the levels of δ-tocotrienol and γ-tocotrienol in T3 extract remain stable for up to 6 months.
ARN estimates the daily exposure to T3 extract based on total intakes from food categories selected from the “What We Eat in America” component of the National Health and Nutrition Examination Survey (NHANES, 2007–2010). ARN reports the two-day average daily food intake for the total U.S. population for the intended food categories to be 939 and 1674 grams per person per day (g/p/day) at the mean and 90th percentile, respectively. Given these intakes, ARN calculates the daily exposure to T3 extract for the intended uses. ARN assumes that a maximum of 50% of the total daily food intake from the intended food categories for a given consumer would contain T3 extract. The mean and 90th percentile exposures to T3 extract from all the intended food categories are 20 mg/p/day (0.3 mg/kg body weight (bw)/day) and 36 mg/p/day (0.5 mg/kg bw/day), respectively, for a 70 kg individual. ARN considers that the use of T3 extract would replace other tocotrienol products used in the intended food categories.
ARN discusses published studies on various tocotrienol extracts to support the safety of T3 extract. These include studies assessing absorption, distribution, metabolism, and excretion (ADME); subchronic and chronic oral toxicity in different animals; tolerance in humans, and genotoxicity.
ARN summarizes published ADME data on tocotrienols from studies conducted in rats and humans. The results of these studies show that the postprandial absorption rates were fastest for α-tocotrienol, followed by the rates for γ-tocotrienol, and then δ-tocotrienol. In humans, the peak plasma concentrations of tocotrienols occurred between three to five hours. The mean elimination half-lives of γ- and δ-tocotrienols were estimated to be 4.3 and 2.3 hours, respectively, and they were undetectable in plasma after 24 hours. The results of these studies show that in both rats and humans, tocotrienols are rapidly absorbed, metabolized, and eliminated.
ARN summarizes several published subchronic oral toxicity studies conducted in mice, chickens, and hamsters for up to 6 weeks using tocotrienol extracts with varying proportions of the four isoforms (α, β, γ, δ). The study authors reported no adverse effects. ARN also discusses two published 13-week subchronic oral toxicity studies in Fisher 344 rats fed diets containing tocotrienol extract purified either from palm oil or rice bran. The study authors reported no mortality and concluded that continuous intake of tocotrienols is safe if consumed at a level less than 0.2% in the rodent diet.
ARN summarizes the results of two published chronic oral toxicity studies conducted in Wistar Hannover rats. The rats were fed diets containing tocotrienol extract (comprised of 36.5% γ-tocotrienol, 8.6% δ-tocotrienol, 24.9% α+β tocotrienol, and 22.7% tocopherols) at concentrations of 0%, 0.08%, 0.4%, or 2% (1% from week 51). In the one-year study, rats fed 2% tocotrienol extract showed significant physiological, hematological, and pathological changes in the livers and deaths occurred. Based on these findings, the study authors determined the no observed adverse effect level (NOAEL) for the tocotrienol extract to be 0.4% in the diet (300 mg/kg bw/day for male rats and 472 mg/kg bw/day for female rats). The two-year chronic toxicity study showed a similar toxicity profile as observed in the one-year study. Based on the histopathological findings in the 0.4% group, ARN considered the NOAEL to be the lower dose of 0.08% (recalculated as 61 mg/kg bw/day and 94 mg/kg bw/day for male and female rats).
In addition, ARN discusses published studies conducted in humans that showed that various forms and amounts of tocotrienols are well-tolerated and do not cause adverse effects at up to 100 mg daily for 6 weeks. ARN also states that in vitro genotoxicity studies indicate that tocotrienols are not mutagenic. In further support, ARN cites GRN 307 palm oil-derived tocols with tocotrienols and α-tocopherol as the principal components) for which FDA had no questions.
Based on the totality of publically available information, ARN concludes that T3 extract is GRAS for its intended uses.
Standards of Identity
In the notice, ARN states its intention to use T3 extract in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. We note that an ingredient that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity.
Potential Labeling Issues
In describing the intended use of T3 extract and in describing some of the information that ARN relies on to conclude that T3 extract is GRAS under the conditions of its intended use, ARN raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Section 403(r) of the FD&C Act lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain T3 extract bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS). The Office of Food Additive Safety (OFAS) neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about T3 extract on the label or in labeling.
Potential Requirement for a Color Additive Petition
In its notice, ARN notes that T3 extract may impart color to food. As such, the use of T3 extract in food products may constitute the use of a color additive under section 20l(t)(l) of the FD&C Act and FDA's implementing regulations in 21 CFR Part 70. Under section 20l(t)(l) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which the Secretary1 by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of a color additive can be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(l) of the FD&C Act and 21 CFR 70.3(f) and (g), the use of a substance that is capable of imparting color may constitute use as a color additive in addition to use as a food additive or GRAS substance. For example, beta-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, beta-carotene is used for both purposes. Importantly, if the use of T3 extract constitutes use as a color additive within the meaning of section 201(t)(l) of the FD&C Act and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FD&C Act requires premarket review and approval of that use by FDA. Under section 402(c) of the FD&C Act, a food product that contains an unapproved color additive would be deemed adulterated.2
In its notice, ARN cites 21 CFR 73.30, under which annatto extract is listed as a color additive for use in human food. FDA recognizes that the composition and manufacturing process for T3 extract are distinct from annatto extract as described in 21 CFR 73.30. If, after receipt of this letter, ARN has any specific questions about this issue, we recommend that ARN contact the Division of Petition Review in OFAS.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of ARN’s notice that T3 extract is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing T3 extract. Accordingly, this response should not be construed to be a statement that foods that contain T3 extract, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by ARN, as well as other information available to FDA, the agency has no questions at this time regarding ARN’s conclusion that T3 extract is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of T3 extract. As always, it is the continuing responsibility of ARN to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000471, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying at www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1The Secretary of the Department of Health and Human Services.
2We note that section 721(b)(4) of the FD&C Act provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FD&C Act while there is in effect a published finding of the Secretary declaring that the substance is exempt from the definition of “food additive” because of its being generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FD&C Act. Importantly, FDA’s response to GRN 000471 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.